Coumadin.RTM., (warfarin sodium) the most widely prescribed anti-thrombotic in North America, results in decreased activity of clotting factors II, VII, IV and X by inhibiting vitamin K epoxide reductase and leads to prolonged coagulation times, measured as INR's. The active component of Coumadin.RTM. (warfarin sodium) is a racemic mixture of the sodium salt chiral coumarin molecule warfarin (1). ##STR3## Considerable differences exist in the metabolic disposition of its two enantiomers. However, only racemic mixtures of S- and R-warfarin (1a and 1b, respectively) are clinically available. This is due to the difficulty of large scale preparation of enantiomerically pure warfarins. ##STR4##
The R- and S-enantiomers of warfarin have been successfully resolved. West et al (J. Am. Chem. Soc. 1961, 81, 2676) used quinidine and quinine salts to obtain enantiomerically pure S- and R-warfarin, respectively. Unfortunately, their procedure had a net yield of 31% based on the amount of racemic warfarin used.
Cook et al (J. Pharmacol. Exp. Ther. 1979, 210(3), 391) derivatized R,S-warfarin with d-10-camphorsulfonyl chloride to give d-10-camphorsulfonates of R,S-warfarin which were separated by column chromatography. The purified R- and S-warfarin camphorsulfonates were converted to R- and S-warfarins upon treatment with 5% sodium hydroxide. The yields of R- and S-warfarin were 10.5% and 12.2%, respectively.
A variety of small scale enrichment or separation methods for racemic warfarin have been reported. Armstrong et al (Anal. Chem. 1994, 66, 4278) reported enantiomeric enrichment of racemic warfarin via adsorptive bubble separation. Using two different derivatized cyclodextrin collectors, enantiomeric excesses of 12% and 20% were obtained. Soini et al (Anal. Chem. 1994, 66, 3477) illustrate separation of racemic warfarin with capillary electrophoresis. Maltodextrin oligosaccharides were shown to separate R- and S-warfarin via an electropherogram. Bargmann-Leyder et al (Chromatographia 1993, 37, 433-443) describe chromatographic resolution of warfarin enantiomers using column liquid chromatography and supercritical fluid chromatography. Chiral stationary phases derived from tyrosine enabled enantiomer resolution. The enantiomeric excesses obtained were not reported. The above-noted procedures would appear to be able to resolve R- and S-warfarin; but, unfortunately, they are either not suitable for industrial scale up or provide insufficient resolution.
Dehydrowarfarin (3, R.sub.1 =phenyl, R.sub.2 =H, R.sub.3 =Me, and R.sub.4-5 =H, shown below) has been identified as a minor metabolite of warfarin and was first isolated and prepared by Kaminsky et al (J. Med. Chem. 1978, 21 (10), 1054). The procedure reported by Kaminsky et al involving copper (I) catalyzed oxidation of warfarin racemate in pyridine was shown by the present inventors to be unreliable and gave at best poor yields (&lt;33%) of dehydrowarfarin.
Highly enantioselective hydrogenations of .alpha.,.beta.-unsaturated ketones have rarely been achieved. Recently, Ohta et al (J. Org. Chem. 1995, 60, 357-363) reported enantioselective hydrogenation of a series of cyclic .alpha.,.beta.-unsaturated ketones using chiral phosphine catalysts. Their hydrogenation procedure failed or provided a very low enantiomeric excess when a phenyl (like that in warfarin) or phenethyl group was present on the olefin. More important to the present invention, if an acyclic .alpha.,.beta.-unsaturated ketone was used, e.g., dehydrowarfarin, the procedure of Ohta et al failed completely.
Thus, the present art is unable to industrially produce enantiomerically pure R- and S-warfarin and its analogs. Therefore, it is desirable to find an industrially useful procedure for the asymmetric synthesis of R and S warfarin and its analogs.